Peripheral Immune Development in Premature Infants with and without NEC

患有和不患有 NEC 的早产儿的周围免疫发育

• 批准号: 10229527
• 负责人: Liza Konnikova
• 金额: $ 23.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229527
• 关键词: Abnormal Cell; Address; Age; Age-Months; Birth; Blood; Blood Volume; Cell Lineage; Cells; Cessation of life; Complex; Complication; Cytometry; Data; Development; Disease; Economic Burden; Etiology; Eye; Fetus; Foundations; Functional disorder; Gestational Age; Goals; High Prevalence; Human; Immune; Immune system; Immunity; Immunological Models; Immunophenotyping; Incidence; Infant; Inflammatory; Intestines; Lead; Life; Maps; Mediating; Metadata; Methodology; Methods; Morbidity - disease rate; Mucosal Immune System; Mus; Natural Immunity; Nature; Necrotizing Enterocolitis; Neonatal; Pathogenesis; Patients; Perinatal; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Population; Predisposition; Premature Birth; Premature Infant; Prevention; Prevention strategy; Regulatory Pathway; Research; Sampling; Second Pregnancy Trimester; Secondary to; Small Intestines; Solid; T memory cell; T-Lymphocyte; Time; Tissues; United States; Very Low Birth Weight Infant; Work; adaptive immunity; cell type; cost estimate; fetal; improved; inflammatory disease of the intestine; interest; machine learning algorithm; macrophage; monocyte; mortality; peripheral blood; premature; prevent; specific biomarkers; systemic inflammatory response; therapy development

Title: Peripheral Immune Development in Premature Infants with and without NEC Abstract: Necrotizing enterocolitis (NEC) is a devastating complication of prematurity that frequently results in death (20- 50%) or severe systemic complications. Although NEC is a multifactorial disease, its precise etiology continues to be poorly understood. As such, there are still no effective prevention methods or treatments available. Given increased intestinal and systemic inflammation seen in NEC, it is likely that the dysregulation of the immune system contributes to its pathogenesis. In order to better understand NEC pathogenesis, it is essential to have a solid understanding of normal immune development that occurs over the first two months of age in premature infants. Our preliminary data obtained from fetuses, patients with NEC and control subjects, show that there is a drastic reduction of total and tissue resident memory T cells in the intestinal tissue and an increase in T cells in the periphery. Moreover, NEC is associated with a significant increase in pro-inflammatory macrophages in intestinal tissue, and a concomitant decrease in circulating monocytes. Recent work has begun to address how neonatal peripheral immunity develops. However, data on the peripheral immune development in premature infants over the first two months of life is sparse. Therefore, the goal of this exploratory proposal is to define normal immune development of premature infants over the first two months of life and characterize its dysregulation in patients with NEC. The overarching hypothesis of this proposal is that development of the peripheral immune system in preterm infants is different in the innate and adaptive immune compartments from that of term infants, and it is this difference that makes them susceptible to NEC. As the blood volume in premature infants is limited, we have developed a methodology to perform deep immunophenotyping on as little as 100 µliters of blood using mass cytometry time of flight (CyTOF). This unique methodology will allow us to address the hypothesis, with the following aims: 1) Define the peripheral immune development of premature infants (<32 weeks) over the first two months of life. We will perform CyTOF on peripheral blood from 50 premature infants, with samples collected at 0, 1, 2, 4, and 8 weeks. Deep characterization of the immune cell landscape and maps of the developmental trajectories of the major cell lineages in premature infants will be generated. 2) Identify peripheral immune cell abnormalities associated with the development of NEC. We will identify dysregulation of immune population trajectories specific to premature infants who develop NEC. This information will provide us with a model for the immune cell mechanism underlying susceptibility to NEC. This project would represent the first detailed deep examination of the development of the immune system in premature infants with and without NEC over the first two months, and will provide sufficient data for the development of a large-scale, in-depth study of the mechanism underlying the development of NEC.

职务名称： 有无NEC早产儿的外周免疫发育 摘要： 坏死性小肠结肠炎（NEC）是早产儿的一种毁灭性并发症，经常导致死亡（20- 30岁）。 50%）或严重的全身性并发症。虽然NEC是一种多因素疾病，但其确切病因仍在继续 不被理解。因此，仍然没有有效的预防方法或治疗方法。给定 NEC中观察到的肠道和全身炎症增加，很可能是免疫调节失调， 系统有助于其发病机制。为了更好地了解NEC的发病机制， 对早产儿出生后头两个月内正常免疫发育的深入了解， 婴儿。我们从胎儿、NEC患者和对照组获得的初步数据显示， 肠组织中总的和组织驻留的记忆T细胞急剧减少， 外围。此外，NEC与促炎性巨噬细胞的显著增加有关， 肠组织，并伴随循环单核细胞减少。最近的工作已经开始解决如何 新生儿外周免疫力发展。然而，关于早产儿外周免疫发育的数据 出生后两个月的婴儿数量很少。因此，本探索性提案的目标是确定 早产儿在生命的头两个月内的正常免疫发育，并表征其 NEC患者中的失调。这项建议的首要假设是， 早产儿外周免疫系统存在先天性免疫和获得性免疫的差异 这是一个巨大的差异，使他们容易受到NEC。作为 早产儿的血容量是有限的，我们已经开发了一种方法， 使用质谱飞行时间（CyTOF）对100微升血液进行免疫表型分析。这种独特 方法学将使我们能够解决这一假设，具有以下目标：1）定义外周免疫 早产儿（<32周）在出生后头两个月的发育。我们将在 来自50名早产儿的外周血，在0、1、2、4和8周收集样品。深 免疫细胞景观的表征和主要细胞发育轨迹的地图 将产生早产儿的谱系。2)识别与免疫相关的外周免疫细胞异常 随着NEC的发展。我们将确定免疫群体轨迹的失调， 发生NEC的早产儿。这些信息将为我们提供一个免疫细胞的模型 NEC易感性的潜在机制。该项目将代表第一次详细深入的审查， 在前两个月内患有和不患有NEC的早产儿的免疫系统发育， 并将提供足够的数据，为发展大规模，深入研究的机制， NEC的发展。

项目成果

Immune dysregulation in Glycogen Storage Disease 1b - a CyTOF approach.

糖原贮积病 1b 中的免疫失调 - CyTOF 方法。

• DOI: 10.21203/rs.3.rs-2598829/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Gehlhaar,Arne;Shouval,Dror;Santiago,EduardoGonzalez;Ling,Galina;McCourt,Blake;Werner,Lael;Yerushalmi,Baruch;Konnikova,Liza
• 通讯作者: Konnikova,Liza

Single cell analysis via mass cytometry of spontaneous intestinal perforation reveals alterations in small intestinal innate and adaptive mucosal immunity.

• DOI: 10.3389/fimmu.2023.995558
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Olaloye O;Eke C;Jolteus A;Konnikova L
• 通讯作者: Konnikova L

Single-cell atlas of the human neonatal small intestine affected by necrotizing enterocolitis.

• DOI: 10.1371/journal.pbio.3002124
• 发表时间: 2023-05
• 期刊: PLoS biology
• 影响因子: 9.8

Renalase and its receptor, PMCA4b, are expressed in the placenta throughout the human gestation.

• DOI: 10.1038/s41598-022-08817-6
• 发表时间: 2022-03-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Wang M;Silva T;Toothaker JM;McCourt BT;Shugrue C;Desir G;Gorelick F;Konnikova L
• 通讯作者: Konnikova L